Benzimidazole derivative compounds and method of making

Abstract

A compound of the formula <IMAGE> I wherein R1-R19 are as described in the specification. The present invention is concerned with benzimidazole derivatives, particularly benzimidazole-2-yl pyridinium compounds of formula I which are pharmaceutically useful in treating or preventing gastric and duodenal ulcers. The invention includes the compounds I, pharmaceutical compositions containing such compounds and the use of such compounds in therapeutic treatment or prevention of gastric and duodenal ulcers.

We claim: 
     
       1. A compound of formula ##STR8## wherein each of R 1 , R 2 , R 3  and R 4  independently is hydrogen, fluorine, chlorine, trifluoromethyl, cyano, a residue of the formula ##STR9## R 5  is hydrogen or a negative charge; each of R 6  and R 8  are hydrogen or lower alkyl; R 7  is lower alkoxy;   R 9  and R 10  each are hydrogen or lower alkyl;   R 11  and R 12  each are lower alkyl; or two of the substituents R 9  and R 10 , or R 9  and R 11 , or R 11  and R 12 , taken together, are a divalent radical of the formula --(CH 2 ) 4  -- or --(CH 2 ) 5  --, and the two remaining substituents of R 9 , R 10 , R 11  and R 12  each are hydrogen or lower alkyl; or R 9  and X together are an additional carbon-carbon bond, R 10  is hydrogen or lower alkyl and R 11  and R 12  each are lower alkyl;   R 13  is lower alkyl;   R 14  and R 15  each are hydrogen or lower alkyl or together with the nitrogen atom to which they are attached form a 5-, 6 , or 7-membered saturated heterocyclic ring;   R 16  is lower alkyl;   X is chlorine, bromine or -OR 17 , or X and R 9  together are an additional carbon-carbon bond;   R 17  is hydrogen, a lower alkanoyl residue or ##STR10## wherein R 18  is a hydrogen or lower alkyl; and   R 19  is hydrogen, lower alkyl, lower alkenyl, lower hydroxyalkyl, lower alkoxy-lower-alkyl, hydroxy-lower-alkoxy-lower-alkyl, lower alkoxy-lower-alkoxy-lower alkyl, hydroxy-lower-alkoxy-lower-alkoxy-lower alkyl, lower-alkoxy-lower-alkoxy-lower-alkoxy-lower-alkyl, lower-alkanoyloxy-lower alkyl or lower-alkanoyloxy-lower-alkoxy-lower-alkyl; whereby the compound as a whole is non-charged or has a single positive charge and whereby in the letter case an external anion is present,     
     
     
       2. The compound of claim 1, wherein each of R 1 , R 2 , R 3  and R 4  is other than chlorine. 
     
     
       3. The compound of claim 1, wherein each of R 1  and R 4  are hydrogen; and each of R 2  and R 3  are fluorine or chlorine. 
     
     
       4. The compound of claim 1, wherein each of R 1  and R 4  are hydrogen; and R 2  is fluorine or trifluoromethyl and R 3  is hydrogen. 
     
     
       5. The compound of claim 4, wherein R 2  is trifluoromethyl and R 3  is hydrogen. 
     
     
       6. The compound of claim 1, wherein R 6  is hydrogen or methyl; R 7  is methoxy or ethoxy; and R 8  is methyl. 
     
     
       7. The compound of claim 6, wherein R 7  is methoxy. 
     
     
       8. The compound of claim 1, wherein each of R 9  and R 10  are hydrogen, each of R 11  and R 12  are methyl and X is chlorine, hydroxy, methoxy, ethoxy, propoxy, butoxy, acetoxy, 2-hydroxyethoxy, 2-methoxyethoxy, 2-(2-hydroxyethoxy)ethoxy, 2-(2-methoxyethoxy)ethoxy, 2-[2-(2-hydroxyethoxy)ethoxy]ethoxy or 2-[2-(2-methoxyethoxy)ethoxy]ethoxy. 
     
     
       9. The compound of claim 8, wherein each of R 9  and R 10  are hydrogen, each of R 11  and R 12  are methyl and X is chlorine, hydroxy, methoxy, ethoxy, propoxy, acetoxy, 2-hydroxyethoxy or 2-methoxyethoxy. 
     
     
       10. The compound of claim 9, wherein each of R 9  and R 10  are hydrogen, each of R 11  and R 12  are methyl and X is ethoxy, acetoxy, 2-hydroxyethoxy or 2-methoxyethoxy. 
     
     
       11. A compound of claim 1, wherein R 9  and X together form an additional carbon-carbon bond, R 10  is hydrogen and each of R 11  and R 12  are methyl, or R 9  and R 11  together are tetramethylene, each of R 10  and R 12  are hydrogen and X is methoxy. 
     
     
       12. The compound of claim 11, wherein R 9  and, X together form an additional carbon-carbon bond, R 10  is hydrogen and each of R 11  and R 12  are methyl. 
     
     
       13. The compound of claim 1 is 2-[[[2-(2-Hydroxyethoxy)-2-methylpropyl]thio]methyl]-4-methoxy-3-methyl-1-[5-(trifluoromethyl)-2-benzimidazolyl]pyridinium methanesulfonate. 
     
     
       14. The compound of claim 1 is intramolecularly deprotonized 2-[[[2-(2-hydroxyethoxy)-2 methylpropyl]thio]methyl]-4-methoxy-3-methyl-1-[5-(trifluoromethyl)-2-benzimidazolyl]pyridinium cation. 
     
     
       15. The compound of claim 1 is 4-Methoxy 2-[[[2-(2-methoxyethoxy)-2-methylpropyl]-thio]methyl]-3-methyl-1-[5-(trifluoromethyl)-2-benzimidazolyl]pyridinium methanesulfonate. 
     
     
       16. The compound of claim 1 is intramolecularly deprotonized 4-methoxy-2-[[[2-(2-methoxyethoxy)-2-methylpropyl]thio]methyl]-3-methyl-1-[5-(trifluoromethyl) 2-benzimidazolyl]pyridinium cation. 
     
     
       17. The compound of claim 1 is 2-[[(2-Acetoxy-2-methylpropyl)thio]methyl]-4-methoxy-3 methyl-1-[5-(trifluoromethyl)-2-benzimidazolyl]-pyridinium methanesulfonate. 
     
     
       18. The compound of claim 1 is 2-[[(2-Acetoxy-2methylpropyl)thio]methyl]-4-methoxy-3-methyl-1-[5-(trifluoromethyl)-2-benzimidazolyl]-pyridinium chloride 
     
     
       19. The compound of claim 1 is Intramolecularly deprotonized 2-[((2-acetoxy-2-methylpropyl) thio]methyl]-4-methoxy-3-methyl-1-[5-(trifluoromethyl)-2-benzimidazolyl]pyridinium cation. 
     
     
       20. The compound of claim 1 is 2-[[(2-Ethoxy2-methylpropyl)thio]methyl]-4-methoxy-3-methyl]-1-[5-(trifluoromethyl)-2-benzimidazolyl]-pyridinium methanesulfonate. 
     
     
       21. The compound of claim 1 is 2-[(2-Ethoxy-2-methylpropyl)thio]methyl]-4-methoxy-3-methyl-1-[5-(trifluoromethyl)-2-benzimidazolyl]-pyridinium chloride. 
     
     
       22. The compound of claim 1 is intramolecularly deprotonized 2-[[(2-ethoxy-2-methylpropyl)thio]methyl]-4-methoxy-3-methyl-1-[5-(trifluoromethyl) 2-benzimidazolyl]pyridinium cation. 
     
     
       23. The compound of claim 1 selected from the group consisting of: intramolecularly deprotonized 2 [[(2-chloro-2-methylpropyl)thio]methyl]-4-methoxy-3-methyl-1-[5-(trifluoromethyl)-2-benzimidazolyl]pyridinium cation; 2-[[(2-chloro-2-methylpropyl)thio]methyl]-4-methoxy-3-methyl-1-[5-(trifluoromethyl)-2-benzimidazolyl]pyridinium chloride; intramolecularly deprotonized 2-[[(2-hydroxy-2-methylpropyl)methyl]-4-methoxy-3- methyl-1-[5-(trifluoromethyl)-2-benzimidazolyl pyridinium cation; intramolecularly deprotonized 4-methoxy-2-[[(2-methoxy-2-methylpropyl)thio]methyl]-3-methyl-1-[5-(trifluoromethyl)-2-benzimidazolyl]pyridinium cation intramolecularly deprotonized 4-methoxy-3-methyl-2-[[(2-methylpropenyl)thio]methyl]-1-[5-(trifluoromethyl)-2-benzimidazolyl]pyridinium cation; intramolecularly deprotonized 4-methoxy-3-methyl-2-[[(2-methyl-2-propoxypropyl)thio]methyl]-1-[5-(trifluoromethyl)-2-benzimidazolyl]pyridinium cation; 4-methoxy-3-methyl-2- [[(2-methylpropenyl)thio]methyl]-1-[5-(trifluoromethyl)-2-benzimidazolyl]pyridinium chloride; and intramolecularly deprotonized 2-[[(2-hydroxy-2-methylpropyl)thio]methyl]-4-methoxy-3,5-dimethyl-2-[5-(trifluoromethyl)-2- benzimidazolyl]pyridinium cation. 
     
     
       24. A anti-ulcer composition for treating or preventing gastric or duodenal ulcers comprising an effective amount of (a) a compound of formula ##STR11## wherein each of R 1 , R 2 , R 3  and R 4  independently is hydrogen, fluorine, chlorine, trifluoromethyl, cyano, a residue of the formula ##STR12## R 5  is hydrogen or a negative charge; each of R 6  and R 8  are hydrogen or lower alkyl;   R 7  is lower alkoxy;   R 9  and R 10  each are hydrogen or lower alkyl;   R 11  and R 12  each are lower alkyl; or two of the substituents R 9  and R 10 , or R 9  and R 11 , or R 11  and R 12 , taken together, are a divalent radical of the formula -( CH 2 ) 4  - or -(CH 2 ) 5  -, and the two remaining substituents of R 9 , R 10 , R 11  and R 12  each are hydrogen or lower alkyl; or R 9  and X together are an additional carbon-carbon bond, R 10  is hydrogen or lower alkyl and R 11  and R 12  each are lower alkyl;   R 13  is lower alkyl;   R 14  and R 15  each are hydrogen or lower alkyl or together with the nitrogen atom to which they are attached form a 5-, 6- or 7-membered saturated heterocyclic ring;   R 16  is lower alkyl;   X is chlorine, bromine or -OH 17 , or X and R 9  together are an additional carbon-carbon bond;   R 17  is hydrogen, a lower alkanoyl residue or ##STR13## wherein R 18  is hydrogen or lower alkyl; and   R 19  is hydrogen, lower alkyl, lower alkenyl, lower hydroxyalkyl, lower alkoxy-lower-alkyl, hydroxy-lower-alkoxy-lower-alkyl, lower alkoxy-lower-alkoxy-lower alkyl, hydroxy-lower-alkoxy-lower-alkoxy-lower alkyl, lower-alkoxy lower-alkoxy-lower-alkoxy-lower-alkyl, hydroxy-lower-alkoxy-lower-alkoxy-lower-alkoxy-lower-alkyl, lower-alkanoyloxy-lower alkyl or lower-alkanoyloxy-lower-alkoxy-lower-alkyl whereby the compound as a whole is non-charged or has a single positive charge and whereby in the latter case an external anion is present, said compound being present in a pharmaceutically effective amount; and     (b) a pharmaceutically acceptable carrier.   
     
     
       25. A method of treating or preventing gastric or duodenal ulcers in a patient comprising administering an effective amount of a compound of formula ##STR14## wherein each of R 1 , R 2 , R 3  and R 4  independently is hydrogen, fluorine, chlorine, trifluoromethyl, cyano, a residue of the formula ##STR15## R 5  is hydrogen or a negative charge; each of R 6  and R 8  are hydrogen or lower alkyl; R 7  is lower alkoxy;   R 9  and R 10  each are hydrogen or lower alkyl;   R 11  and R 12  each are lower alkyl; or two of the substituents R 9  and R 10 , or R 9  and R 11 , or R 11  and R 12 , taken together, are a divalent radical of the formula --(CH 2 ) 4  -- or --(CH 2 ) 5  --, and the two remaining substituents of R 9 , R 10 , R 11  and R 12  each are hydrogen or lower alkyl; or R 9  and X together are an additional carbon-carbon bond, R 10  is hydrogen or lower alkyl and R 11  and R 12  each are lower alkyl;   R 13  is lower alkyl;   R 14  and R 15  each are hydrogen or lower alkyl or together with the nitrogen atom to which they are attached form a 5-, 6- or 7-membered saturated heterocyclic ring;   R 16  is lower alkyl;   X is chlorine, bromine or --OR 17 , or X and R 9  together are an additional carbon-carbon bond;   R 17  is hydrogen, a lower alkanoyl residue or ##STR16## wherein R 18  is hydrogen or lower alkyl; and   R 19  is hydrogen, lower alkyl, lower alkanoyl, lower hydroxyalkyl, lower alkoxy-lower-alkyl, hydroxy-lower-alkoxy-lower-alkyl, lower alkoxy-lower alkoxy-lower alkyl, hydroxy-lower-alkoxy-lower-alkoxy-lower alkyl, lower-alkoxy lower-alkoxy-lower-alkoxy-lower-alkyl, hydroxy-lower-alkoxy-lower-alkoxy-lower-alkoxy-lower-alkyl, lower-alkanoyloxy-lower alkyl or lower-alkanoyloxy-lower-alkoxy-lower-alkyl whereby the compound as a whole is non-charged or bas a single positive charge and whereby in the latter case an external anion is present.     
     
     
       26. The method of claim 25 wherein said compound is orally administered to the patient in a daily dosage of about 30 to about 400 mg. 
     
     
       27. The method of claim 25 wherein said compound is intravenously administered to the patient in a daily dosage of about 30 to about 400 mg.